The OBR Blog

From among 4,500 abstracts to be presented at this year’s ASCO, an official pre-ASCO press cast featured results of 5 chief clinical trials. Regarding the press cast, Michael Link, MD, President of ASCO, said, “Today’s studies demonstrate improvements in precision medicine that identify and exploit cancer’s genetic weak spots to halt tumor growth and in some cases eradicate disease. Other studies give us valuable new tools and information to lessen the short- and long-term side effects of cancer treatment for our patients.”

Pre-adjuvant Abiraterone Treatment
In a randomized Phase 2 trial, 6 months of treatment with abiraterone [Zytiga; Jansenn Biotech] along with hormonal therapy given prior to prostatectomy to men with high-risk early prostate cancer eradicated cancer cells in about one-third of patients. Abiraterone is currently FDA approved for metastatic prostate cancer. This trial was conducted in the pre-adjuvant setting.

The study included 58 men with 1 or more of these high-risk features:
• Gleason score 8-10 (71% of men)
• PSA level >20 ng/ml (19%)
• T3,T4 bulky disease (24%)
• High PSA velocity (16%)
• Extra nodal disease could be included

Patients were randomized to receive 3 months of treatment with leuprolide alone or 3 months of leuprolide plus abiraterone plus low-dose prednisone. After 3 months of treatment, all patients in the trial were treated for another 3 months of neoadjuvant therapy with abiraterone, leuprolide, and prednisone. After of 6 months of neoadjuvant therapy, radical prostatectomy was performed and pathological response evaluated.

pCR was 10% for those treated with abiraterone for 6 months vs 4% for those who received leuprolide for 3 months and then abiraterone for 3 months, and near pCR was observed in 24% and 11%, respectively. Total response rate was 34% vs 15%, respectively; the difference between groups was not statistically significant.

“These results are particularly amazing in this incredibly high-risk group of patients, and suggest that this combination therapy could improve outcomes for a substantial number of men, said lead author Mary-Ellen Taplin, MD, Harvard Medical School and the Dana-Farber Cancer Institute, Boston, MA. Larger, longer trials are needed to confirm this approach (i.e., neoadjuvant use of abiraterone plus hormones plus prednisone).

Combining a BRAF inhibitor and a MEK1 inhibitor in Advanced Melanoma
Results of an early Phase 1B trial found that combining two investigational oral targeted therapies—the BRAF inhibitor dabarafenib and the MEK inhibitor trametinib—appeared to halt disease progression in patients with metastatic melanoma. The lead author of the study, Jeffrey Weber, MD, of H. Lee Moffitt Cancer Center, Tampa, FL., went on to say that while not a comparative study there were different side effects than those reported with a single-agent BRAF inhibitor.

About 50% of all melanomas harbor a mutation in the BRAF gene, and the related MEK pathway is highly active in those patients, providing a rationale for the dual targeted approach. The Phase 1B study included a subset of 77 patients with advanced melanoma who were enrolled in a larger 4-part study. The trial identified the following dose as recommended for further study: dabarafenib 150 mg/trametinib 2 mg.

Again noting that this was not a comparative study, Dr. Weber said that use of the combination significantly decreased skin toxicity if one compared these results with those reported with BRAF inhibitors. For example, only 3% of patients developed squamous cell carcinomas compared with about 15% to 25% of patients treated with other BRAF inhibitors; another 5% developed actinic keratosis which is much lower than with a BRAF inhibitor alone, Dr. Weber commented. Pyrexia was the only side effect that was slightly higher with the combination and this tended to occur along with chills, fatigue, and nausea; grade 3 pyrexia was reported in 8% of patients.

Using a waterfall plot to assess tumor shrinkage on the combination therapy, Dr. Weber said: “This is among the best results I’ve seen. About 95% of patients had stable disease, partial response, or complete response.” Median PFS was 10.8 months, which he called “extremely encouraging.”

“This is the first Phase 3 study to show that a treatment is effective for breakthrough CINV, which afflicts about 50% to 60% of patients taking highly emetogenic chemotherapy,” said lead author Rudolph Navari, MD, Indiana University School of Medicine, South Bend, IN.

The study enrolled 205 chemotherapy-naïve patients treated with cisplatin, doxorubicin, and cyclophosphamide. All patients received guideline-recommended drugs to prevent nausea and vomiting, but 80 patients experienced breakthrough CINV and were randomized to olanzapine (n=42) or metoclopramide (n=38) for 72 hours of treatment.

Control of emesis was achieved in 71% of those treated with olanzapine vs 32% of the metoclopramide group; nausea was controlled in 67% and 24%, respectively. Both of these results were statistically significant (P<.01); no grade 3 or 4 toxicity was observed in either group.

Crizotinib in ALK-driven Pediatric Tumors
An early Phase 1 study suggests that Pfizer’s crizotinib (Xalkori, approved to treat lung cancer) may be an effective approach to anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors (IMT), and neuroblastoma in select children with aggressive forms of these cancers, which commonly have ALK gene abnormalities, said lead author Yael Mosse, MD, Children’s Hospital of Philadelphia, PA.

ALK gene abnormalities are present in 80% to 95% of ALCL cases, 50% of IMT cases, and 10% to 15% of aggressive neuroblastomas. The study included 70 children with these cancers who had progressed on standard therapies. Patients received one of 6 different doses of oral crizotinib twice daily and stayed on the drug until it was no longer well tolerated.

In ALCL, 88% (7/8) patients experienced complete response, with no detectable disease for as long as 18 months. The majority of 7 patients with IMT experienced effects ranging from tumor shrinkage to complete tumor regression. Of the 27 patients with neuroblastoma, 8 had known ALK mutations; of these, 2 of 8 had complete response, 2 had minor responses, and 1 had stable disease. Responses were also seen among 19 neuroblastoma patients with unknown ALK status; 1 complete response and 6 with prolonged stable disease.

The high degree of activity seen with crizotinib in these childhood tumors will lead to larger trials in ALCL and other childhood tumors, said Dr. Mosse.

Knowledge Gap About Late Effects of Chemotherapy Among Primary Care Providers
A large survey of 1,072 primary care providers (PCPs) and 1,030 medical oncologists who treat breast and colorectal cancer revealed a troubling knowledge gap among the PCPs regarding late effects of chemotherapy in cancer survivors. The survey asked questions about four commonly used chemotherapy agents: doxorubicin, cyclophosphamide, paclitaxel, and oxaliplatin.

Among PCPs, 55% correctly identified cardiac dysfunction as a late effect of doxorubicin compared with 95% of oncologists; 26% of PCPs correctly identified peripheral neuropathy as a late effect of paclitaxel compared with 97% of oncologists; 22% of PCPs correctly identified peripheral neuropathy as a late effect of oxaliplatin compared with 96% of oncologists. For cyclophosphamide, premature menopause was correctly identified as a late effect by 15% of PCPs and 71% of oncologists, and secondary malignancy was correctly identified as a late effect by 17% of PCPs and 62% of oncologists.

Lead author, Larissa Nekhlyudov, MD, Harvard Medical School, Boston, MA, noted that with more than 12 million cancer survivors, late effects of chemotherapy are becoming increasingly important. She said that survivorship plans should address this knowledge gap and relay information to patients and to PCPs so that they can provide optimal management to cancer survivors.

Kantar Health, a leading global oncology consultancy, has identified several pivotal clinical trials that will be presented at the upcoming American Society of Clinical Oncology (ASCO) conference, which have the potential to significantly alter the treatment paradigm in several tumor types. A brief synopsis of some of those trials and an evaluation of the data expectations are discussed. For a full discussion of all 9 top picks, please see the associated article in the May issue of OBR Green.

A mere four months after its approval in April 2011, Zytiga had captured approximately one-quarter of the patient share in the second-line CRPC market (Kantar Health, CancerMPact® Treatment Architecture 2011), and utilization continues to grow. The COU-AA-302, an international Phase 3 study, aims to move Zytiga into first-line. The study compares Zytiga plus prednisone with placebo plus prednisone in 1,088 asymptomatic or minimally symptomatic, chemotherapy-naive CRPC patients. In March, Janssen announced that the Independent Data Monitoring Committee (IDMC) unanimously recommended unblinding the study and offering Zytiga to patients in the placebo arm. While news of early unblinding is very promising, the subsequent patient cross-over may ultimately confound OS which could hamper the approval process down the road if a strong enough signal wasn’t already evident at the interim analysis. COU-AA-302, Abstract LBA4518, Saturday, June 2, 8:00 am

T-DM1 (Trastuzumab emtansine, Genentech/Roche) in HER2+ Breast Cancer

The concept behind T-DM1 is exciting – adding the benefit of chemotherapy to the specificity of targeted therapy, thereby decreasing normal chemotherapy-associated toxicities – which could lead to treatment paradigm changes if successful. Currently, three Phase 3 trials are examining the efficacy and safety of T-DM1 in first-line (MARIANNE), second-line (EMILIA), and third line (TH3RESA), of which EMILIA is expected to support initial launch. In March 2012, Genentech announced top-line results from the EMILIA trial, indicating improved PFS in patients treated with T-DM1 compared with those treated with Tykerb [lapatinib; GlaxoSmithKline] plus Xeloda [capecitabine; Roche] in 991 HER2+ breast cancer patients who had previously received treatment with Herceptin and a taxane.

Last years’ FDA revocation of Avastin’s [bevacizumab; Genentech/Roche] approval in breast cancer has raised awareness about the need for meaningful PFS or OS benefits in this disease. With this in mind, all eyes are going to be on the magnitude of PFS benefit produced in EMILIA, especially considering that any overall survival (OS) data presented at ASCO will be immature. EMILIA, Abstract LBA1, Sunday June 3, 1:45pm, Plenary

Like ASCO 2011, ASCO 2012 is an exciting year for melanoma. GSK is presenting the results of two of their pipeline drugs, the B-Raf inhibitor dabrafenib and the MEK inhibitor trametinib.. In January 2011, GSK initiated a phase III trial (BREAK-3) to evaluate dabrafenib versus dacarbazine in 249 previously untreated Stage III/IV melanoma patients harboring BRAF V600E mutation. The fact that this trial is reporting out less than 18 months after initiation speaks to the enthusiasm of the melanoma community for targeted agents, something which didn’t exist 2 years ago, prior to the development of Yervoy [ipilimumab; Bristol-Myers Squibb] and Zelboraf [vemurafenib; Genentech/Roche].

This new found enthusiasm also includes increasing interest in MEK inhibitors, and GSK’s trametinib is the front-runner in development. In February, GSK announced that the Phase 3 METRIC study in 297 patients with advanced melanoma harboring a BRAF V600E/K mutation met the primary endpoint of prolonging PFS compared with chemotherapy. Details on the magnitude of benefit were not disclosed; and there had been speculation that MEK inhibitors would not be very efficacious as monotherapies, so the press release announcing positive results in METRIC is a welcome surprise.

In order for dabrafenib or trametinib to compete in the marketplace they will need to improve on impressive benchmarks set by Zelboraf — the BRIM3 trial showed 48% ORR, 5.3 month PFS, and 84% six-month OS — and/or show decreased levels of drug resistance or improved safety. If the monotherapies demonstrate lackluster efficacy, dabrefenib and trametnib could have a future in combination with each other — GSK is testing this combination in BRAF mutant metastatic melanoma patients; however this development is still in Phase II (to learn more stay after the METRIC presentation for Abstract 8510). BREAK-3, Abstract LBA8500, Monday, June 4, 8:00 am; METRIC, Abstract LBA8509, Monday, June 4, 3:15 pm

Of interest: updated OS results for Zelboraf in the BRIM3 trial a mere 15 minutes after the BREAK-3 presentation, at 8:30 am

These and other picks are outlined in the table below.

Kantar Health’s Top Presentations of Interest, ASCO 2012

Agent

Indication

Abstract

Date and Time

Zytiga

CRPC, chemotherapy-naive

LBA4518

Saturday,8:00am

Tivozanib

RCC, first-/second-line

4501

Saturday, 3:15pm

Avastin

Ovarian Cancer, platinum-resistant

LBA5002

Saturday, 3:30pm

Avastin

CRC, second-line

CRA3503

Sunday, 10:45am

T-DM1

HER2+ Breast Cancer, refractory

LBA1

Sunday, 1:45pm

Dabrafenib

Melanoma, first-line, B-RAF mutants

LBA8500

Monday, 8:00am

Trametinib

Melanoma, first-line, B-RAF mutants

LBA8509

Monday, 3:15pm

Cabozantinib

Thyroid Cancer, Medullary

5508

Monday, 11:30am

Afatinib

NSCLC, first-line, EGFR mutant

LBA7500

Monday, 3:00pm

Following the 2012 ASCO meeting, Kantar Health will publish an article in Oncology Business Review to provide a synopsis of some of the most interesting next-generation agents and therapeutic approaches in development.

Roundtable sessions at NCCN meetings get to the heart of today’s oncology issues. The topics are diverse and offer differing perspectives from panelists who bring broad insights to prevalent discussions. For example, a roundtable at the recently held NCCN annual meeting titled, “Cancer in Corporate America – Business as Usual?” explored the role of US corporations in today’s health and cancer care continuum.

Our system of having employers providing health insurance is fairly unique as compared with the single payer systems in Europe and elsewhere. In this roundtable discussion, moderated by the veteran ABC News correspondent Sam Donaldson, the high cost of cancer care is a given, and the panel moved beyond that issue to discuss the role an employer has in covering the cost of cancer care.

According to Donaldson, “58% of non-elderly people in the US get their primary health insurance from their employers,” and he asked the panel to discuss just what does business as usual mean in this case, and what does an employer owe its employees? As the cost of cancer and healthcare continues to rise, it could be the employer that is thrust to the center of the debate.

Robert W. Carlson, MD, of Stanford Cancer Institute, Stanford CA, pointed out that almost always when someone is diagnosed with cancer, the first question he or she asks is “How will this change my life?” But, to Carlson, what that person is really asking is: What does this mean to my job security? Is my insurance adequate? And, will my employer discriminate? To answer Donaldson’s question, Carlson said that “Businesses owe their employees support both professional (your job is safe) and emotional (such as a phone call from the employer).”

Following up on that thought, Helen Darling, President, CEO of the National Business Group on Health, a non-profit organization devoted exclusively to representing large employers’ perspective on national health policy issues, said that “employees are the only appreciable asset a company has, most every other asset depreciates over time, and great companies invest in their employees.” That investment, she indicated, includes healthcare coverage for cancer. She says that companies have to be sure that employees have the tools and resources they need when diagnosed with cancer.

Practical in his perspective, J. Randall MacDonald, Senior VP of HR at IBM, which employs more than 500,000 people with healthcare benefits, said that “investing in employees is a business proposition. A healthy employee is a productive employee, and a productive employee is an innovative employee.” MacDonald believes that patients, providers, and plans all need to collaborate with each other in order to provide a means of prevention, detection, and evidence-based medicine to deal with health concerns effectively.

But, Sheri McCoy, Vice Chairman of the Executive Committee of Johnson & Johnson offered that in order to move from disease care to preventive care, education and an environmental shift is required. For instance, at J&J, she informed, they have eliminated all smoking in the workplace, they focus on healthy diet, and the company has put gyms and fitness centers throughout the workplace. “These tactics help us achieve a return on investment with employees,” she concluded.

The Goodyear Tire & Rubber Company, represented by J. Brent Pawlecki, MD, said that their company goal is to have healthy, engaged, productive employees. In order to meet these goals, he says, Goodyear plans on providing prevention whenever possible, and when prevention isn’t possible to get employees into the right care, and when the right care is no longer available, the company plans to ensure a dignified and respectful exit. Mr. Pawlecki says that “corporate America has covered prevention and treatment well enough, but that Goodyear and others need to do more to help employees with the inevitable.”

At this point in the discussion, Mr. Donaldson shifted the emphasis of the panel over to the cost of healthcare coverage.

According to MacDonald, out of the roughly $1.2 billion IBM spends on healthcare benefits, about $110 million of that is for cancer care. “Obviously, IBM has to pay attention to cost, and is trying to reduce healthcare costs. Oftentimes, controlling costs leads to very difficult decisions,” but, MacDonald thinks that IBM has the best interests of the employee in mind.

Discussing the important topic of waste, Darling said that “we know that there is something around 20%-30% waste in the healthcare system” and removing that waste would allow more room for effective care.

Dr. Carlson responded that Stanford struggles with costs almost every day, and those struggles are mostly related to structures such as prior authorizations overlaid on the medical system to control costs while adhering to evidence-based medicine. He added that companies are usually advocates for employees, and that when it comes to controlling costs, companies are mostly negotiating coverage with insurance providers.

He provided a case example of a woman with breast cancer whose insurance company would not provide coverage of an FDA-approved regimen or coverage of any breast cancer therapy that was not generic, meaning the patient could not take advantage of any of the new breast cancer agents and regimens. “Perhaps an extreme example,” he said, “but discouraging nonetheless.” In this case, the manufacturers “stepped up to the plate” and provided the medication free of charge.

When the discussion moved into healthcare reform, Kavita Patel, MD, MSHS, of the Brookings Institution’s Engelberg Center for Health Care Reform was given the opportunity to bring her unique perspective to the panel. Mr. Donaldson asked, “If you’re a cancer patient, does the ACA help you?” Dr. Patel thought it helped immediately, because the ACA removes the opportunity for a health insurance company to not accept a person into their plan because of a pre-existing condition. “They call it an even playing field now because this stipulation makes private insurance just as accountable as employer-based insurance,” she said.

Insurance exchanges, said Dr. Patel, “will help cancer patients because the ACA allows you to purchase insurance that is not outrageously expensive if you don’t qualify for Medicare/Medicaid and you do not work for a company that provides health insurance. Unfortunately most of these people can only afford catastrophic care in the current system.”

Although the new ACA law will not go into full effect until 2017, Donaldson asked the panel if they liked the ACA provisions. Ms. Darling made the point that it is a big step forward for uninsured people to gain access to insurance coverage.

What bothers Mr. MacDonald of IBM is not the content of ACA, but the unknown. For example, multi-state employers like IBM have a single control point at the federal level rather than having 50 different benefit departments. He says that they are worried that some of the ability to control healthcare will be delegated to the States and they may ignore the federal regulations; especially when it comes to healthcare exchanges and the employer’s only recourse is to sue the State to protect the employee. Then there is the perception that the employer is therefore against healthcare. Managing the unknown can get expensive.

Analysis
As legislators, justices, doctors, insurance companies, employers, and importantly patients struggle with how to manage the burden of cost in the US healthcare system, it is clear that there isn’t a easy answer and that sacrifices will need to be made. One thing about this particular panel is that there seemed to be agreement that some employers are doing the right thing in providing coverage and advocating for employees, and that there is hope that all companies in the US will follow those providing excellent examples.